Bridging the Gap: A Reticulo-Propriospinal Detour Bypassing an Incomplete Spinal Cord Injury

Abstract

Anatomically incomplete spinal cord injuries are often followed by considerable functional recovery in patients and animal models, largely because of processes of neuronal plasticity. In contrast to the corticospinal system, where sprouting of fibers and rearrangements of circuits in response to lesions have been well studied, structural adaptations within descending brainstem pathways and intraspinal networks are poorly investigated, despite the recognized physiological significance of these systems across species. In the present study, spontaneous neuroanatomical plasticity of severed bulbospinal systems and propriospinal neurons was investigated following unilateral C4 spinal hemisection in adult rats. Injection of retrograde tracer into the ipsilesional segments C3-C4 revealed a specific increase in the projection from the ipsilesional gigantocellular reticular nucleus in response to the injury. Substantial regenerative fiber sprouting of reticulospinal axons above the injury site was demonstrated by anterograde tracing. Regrowing reticulospinal fibers exhibited excitatory, vGLUT2-positive varicosities, indicating their synaptic integration into spinal networks. Reticulospinal fibers formed close appositions onto descending, double-midline crossing C3-C4 propriospinal neurons, which crossed the lesion site in the intact half of the spinal cord and recrossed to the denervated cervical hemicord below the injury. These propriospinal projections around the lesion were significantly enhanced after injury. Our results suggest that severed reticulospinal fibers, which are part of the phylogenetically oldest motor command system, spontaneously arborize and form contacts onto a plastic propriospinal relay, thereby bypassing the lesion. These rearrangements were accompanied by substantial locomotor recovery, implying a potential physiological relevance of the detour in restoration of motor function after spinal injury.

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury

“…Additional perspective may be gained by characterizing the intrinsic proteomic mechanisms driving compensatory sprouting of both injured and intact CNS projections following injury (175). This includes corticospinal (176 -178), rubrospinal (179), reticulospinal, and propriospinal axons (180,181). Finally, exploring the identified signaling networks activated within injured CNS neurons that regenerate into permissive cellular grafts discussed below may yield novel insight into the molecular switches that enable growth of an axon previously incapable of regeneration.…”

New Aspects of Graft-induced Central Plasticity and Neuroregeneration at T 10 in a Rat Model†

“…Until now, traumatic paraplegia by severance of the spinal cord (SC) remains an irreversible condition. Basically, current clinical treatment strategies are targeted to promote axon regeneration and outgrowth beyond the scar formation following SC avulsion [1][2][3][4][5][8][9][10][11][12][13][14][15][16][17][18][20][21][24][25][26][27][28][29][30][31][72][73][74][75][76][77][78][79][80][81][82][83][84][85] Previous experimental and clinical studies together with GB have aroused some hope that paraplegic patients might achieve some selective voluntary muscle reinnervation after grafting the first motor neuron to skeletal hip muscles [10,11,25,72,73].…”

“…In all FB+ cases, the FB+ neurons were observed in ipsilateral lamina 9 -multipolar, up to 100 µm=alpha motor neurons; in two positive cases (No 10 and 13), FB+ neurons were also identified in other laminae (e.g., lamina 4, 5, 7) and in the dorsal nucleus Clarke-sensitive neurons and interneurons. Filli and coworkers suggest [74] that "severed reticulo-spinal fibers, which are part of the phylogenetically oldest motor command system, spontaneously arborize and form contacts onto a plastic propriospinal relay, thereby bypassing the lesion" quote end. These rearrangements were accompanied by substantial locomotor recovery, implying a potential physiological relevance of the detour in restoration of motor function after spinal injury" [75].…”

Identification of residual descending pathways after human spinal cord injury.

“…While human studies in SCI have primarily focused on corticospinal tract function (Wolfe, 1996, McKay et al, 1997, Curt et al, 1998, Curt et al, 2004, Curt and Ellaway, 2012, animal models of SCI have provided evidence that long descending propriospinal pathways can participate in synaptic plasticity, forming so-called detour pathways which re-establish functional cortical connections with the lumbosacral motor circuitry, ultimately leading to recovery of motor function (Bareyre et al, 2004, Courtine et al, 2009, Lang et al, 2012, Filli et al, 2014.…”

“…Further, following incomplete SCI in animal models, propriospinal neurons have been shown to play a role in re-establishing supraspinal influence on spinal circuits caudal to the injury (Bareyre, Kerschensteiner et al 2004, Courtine, Song et al 2008, Filli, Engmann et al 2014, accomplished by the sprouting of severed cortico-and reticulospinal axons to establish synaptic contacts with propriospinal neurons, which then relay the descending signal around the zone of injury. The current study examined the relationship between descending interlimb pathways and volitional muscle activation below the level of lesion.…”